Tripeptides of N3 -4-methoxyfumaryl-L-2,3-diaminopropanoic acid

ABSTRACT

The subject of this present invention is tripeptides of N 3  -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR1## where R is a hydrogen atom when R 1  is the dipeptide residue containing the residue of alanine, methonine, valine, leucine or norvaline, or R and R 1  have the same meaning and are the residue of monoaminomonocarboxylic aminoacid, such as those of alanine, methionine, valine, leucine, or norvaline, or R is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid, and R 1  is a hydroxide group, and the method of their obtaining. The method of obtaining involves converting N 2  -tetrbutoxycarbonyl, N 3  -4-methoxyfumaroyl-L-2,3-diaminopropanoic acid into an active ester which is used for acylating a dipeptide or N 2  -tetr-butoxycarbonyl, N 3  -4-methoxyfumaryl-L-2,3-diaminopropanoic acid into an active ester which is used for acylating the aminoacid whereafter the protection of the amino group is removed and the latter is acylated with an active ester of the N-protected aminoacid or N 3  -4-methoxyfumaryl-L-2,3-diaminopropanoic acid is acylated with an active ester of the N-protected dipeptide and the protection of the amino group is removed from the obtained N-protected tripeptide in the medium of a non-polar organic solvent or its mixture with water, whereas the final product in the form of a salt is isolated by being crystallized or being converted into a free acid.

The subject of this present invention is tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR2## where R is a hydrogen atom when R₁ is a dipeptide residue containing a residue of alanine, methionine, valine, leucine, norvaline, or R and R₁ have the same meaning and mean the residues of monoaminomono-carboxylic aminoacid, such as that of alanine, methionine, valine, leucine, norvaline, or R is the residue of dipeptide containing the residues of alanine, methionine, valine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3-diaminopropionic acid and R₁ is a hydroxyl group, and the method of their obtaining.

Dipeptides containing derivatives of L-2,3-diaminopropanoic acid are known until now and the method of their obtaining involves acylation of N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid with an active ester of N-protected aminoacid, the reaction taking place in the medium of an organic solvent at room temperature (R. Andruszkiewicz, H. Chmara, S. Milewski and E. Borowski, J. Med. Chem., 30, 17-15-1719/1987).

On the other hand, tripeptides are not known which show high antifungal activity and contain derivatives of L-2,3-diaminopropanoic acid.

The essence of this present invention are tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR3## where R is a hydrogen atom when R₁ is a dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, or R and R₁ have the same meaning and mean the amino residue of monoaminomonocarboxylic amino acid, such as those of alanine, methionine, valine, leucine, norvaline, or R means the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3dipropanoic acid and R₁ means a hydroxide group.

According to this present invention the method of obtaining tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR4## where R is a hydrogen atom and R₁ is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, or norvaline involves converting of N² -tertbutoxycarbonyl, n³ -4-methoxyfumaryl-L-2,3-diaminopropanoic to an active ester which is used for acylation of the dipeptide in the medium of a polar organic solvent or its mixture with water, whereas the final product in the form of a salt is isolated by being crystallised or converted into a free acid.

N-hydroxysuccinoimide is the agent activating N² -tertbutoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid.

Tetrahydroxyfurane or a mixture of a monohydric aliphatic alcohol with a C1-C5 chain length and water is used as an organic solvent.

According to this present invention, the method of obtaining tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid of the general formula ##STR5## where R₁ and R are the residue of monoaminomonocarboxylic amino acid, such as these of alanine, methionine, valine, leucine or norvaline involves converting N² -tert-butoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid into an active ester which is used for acylating monoaminomonocarboxylic aminoacid whereafter the protection of the amino group is removed and the latter is acylated with an active ester of N-protected monoaminomonocarboxylic aminoacid in the medium of a polar organic solvent, or its mixture with water, whereas the final product in the form of a salt is isolated by being crystallised and, possibly, converted into a free acid.

N-hydroxysuccinoimide is an agent activating N² -tert-butoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid and N-protected monoaminocarboxylic aminoacid.

Tetrahydrofurane or a mixture of monohydric aliphatic alcohol with a C1-C5 chain length and water is used as a polar organic solvent.

According to this present invention, the method of obtaining tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid of the general formula ##STR6## where R is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid and R₁ is a hydroxide group involves acylating N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid with an active ester of N-protected dipeptide in the medium of a polar organic solvent or its mixture with water, whereafter the amine group protection is removed from the tripeptide thus obtained and the final product in the form of a salt is isolated by being crystallised and, possibly, being converted into a free acid.

N-hydroxysuccinoimide is the agent activating the N-protected monoaminomonocarboxylic aminoacid.

Tetrahydrofuran or a mixture of monohydric (monohydroxyl) aliphatic alcohol with a C1-C5 chain length and water is used as a polar organic solvent. The compounds in question show an antimicrobial activity, patricularly an antifungal activity relating to pathogenic fungi, such as Candida albicans, Cryptococens neoformans and Aspergillus spp., whereas their essential advantage is the observed lower frequency of occurrence of spontaneous mutants, microorganisms resistant to the action of tripeptides in comparison to the mutants resistant to the action of dipeptides.

The above has been assumed to be related to the difference in the specificity of action of the so-called permeases transporting peptides to cells of microorganisms.

The antifungal activity has been evaluated, by the example of N² -L-methionyl-L-norvalyl-N³ -4-methoxyfumaryl-L-2,3-diaminopropropanoic acid during the in vitro and in vivo tests conducted on experimentally infected mouse models.

The in vitro activity has been evaluated by the method of serial dilutions in parallel on solid YNB medium and on YNB w/o+AN medium, where the abbreviation AN means 200 mg of sodium glutamate, 10 mg of L-histidine, 20 mg of DL-methionine, 20 mg DL-tryptophane, 10 g of glucose and 15 g of agar-agar per 1 liter of the YNB medium. The application of the medium modified in such a manner was made necessary by the known phenomenon of lower biological activity in the media containing ammonium sulphate as a source of nitrogen.

In evaluating the activity allowance has been made for the value ranges of the minimum inhibitory concentrations the growth of strains (MIC in mg/liter), the cummulative percentages of the strains hampered by a definite mean geometric concentration of the value of MIC (G_(MIC)), the values of the concentrations hampering the growth of 50 and 90 per cent of the tested strains (MIC₅₀ and MIC₉₀) representing the species Candida albicans (n=50), other species of the genus Candida (Candida spp., n=117) and the entire genus Candida (n=167). 167 strains of the genus Candida have been freshly isolated from hospitalised patients. The table presented below shows the activity of N² (-L-methionyl-L-norvalyl)N³ -(4-methoxyfumaryl)-L-2,3-diaminoproprionic acid for 167 strains of the genus Candida isolated from patients.

    __________________________________________________________________________     /48 h - 37° C./                                                                           MIC                                                                Number      value                                                              of          range,                                                       Species                                                                              strains                                                                             Substrate                                                                             mg/liter                                                                            G.sub.MIC                                                                           MIC.sub.50                                                                          MIC.sub.90                                    __________________________________________________________________________     C. albicans                                                                          50   YNB    0.006-100                                                                           39.5 120.1                                                                               180.6                                                    YNB w/O +                                                                             0.006-100                                                                           3.3  0.6  149.8                                                    AN                                                                  Candida                                                                              117  YNB    0.006-100                                                                           68.9 127.5                                                                               182.8                                         spp.       YNB w/O +                                                                             0.006-100                                                                           6.9  2.9  162.5                                                    AN                                                                  Total 167  YNB    0.006-100                                                                           58.3 125.4                                                                               182.2                                                    YNB w/O +                                                                             0.006-100                                                                           5.5  1.4  159.4                                                    AN                                                                  __________________________________________________________________________

For one of the elected strains of Candida albicans ATCC 26278, the minimum inhibitory concentration, MIC, amounted to 0.4 mg/liter in the case of N² (-methionyl-L-norvalyl), N³ -methoxyfumaroyl-L-2,3-diaminopropanoic acid and to 0.02 mg/liter for N² (-L-lysyl-L-norvalyl), N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-2,3-diaminopropanoic acid.

The derivatives show a high therapeutic efficiency. The therapeutic efficiency was evaluated by the example of N² (-L-methionyl-L-norvalyl), N³ -4-methoxyfumaryl-L-2,3diaminopropanoic acid (Met-Nva-FMAP).

During the in vivo tests was used of the model of generalised candidiosis with the Swiss mouse. The mice were infected intravenously with the strain Candida albicans 162. The infecting dose amounted to 2×10⁷ cfu per 1 gm of body weight. The therapeutic efficiency was evaluated by mathematically determining protective doses (PD₅₀), curative doses (CD₅₀), and by quantitative mycological evaluation of the kidneys of the Swiss mice infected with experimental candidiase.

By way of example, a protective dose, PD₅₀, of 0.374 mg/kg has been determined for the Met-Nva-FMAP tripeptide for 5-9 days of observation, whereas curative doses, CD₅₀, determined for 9 and 16 days of observation amounted to 0.499 and 1.062 mg/kg, respectively.

The quantitative evaluation of the kidneys of the nice infected and cured with a dose of 10×CD₅₀ /g, i.e. 4.99 mg/kg, of the Met-Nva-FFMAP tripeptide showed that the number of the cells of Candida albicans was markedly reduced on the 6th day as compared with a control group.

Tripeptides of N³ -4-methoxyfumaryl-L-2,3-diaminopropionic acid and the method of their obtaining are illustrated by the examples provided below.

EXAMPLE I

a. 2.065 g/5 mM/ of N-hydroxysuccinoimide ester of N² -t-butoxycarbonyl, N³ -4methoxyfumaryl-L-2,3-diaminopropanoic acid in 10 ml of tetrafurane are added to a solution of 1.1 g (5mM) L-methionyl-L-alanine and 0.42 g (5 mM) of sodium hydrogen carbonate in 15 ml of water under intensive mixing and are allowed to stand for 6 hours. Next, the solvent is evaporated, the residue dissolved in 10 ml of water and acidified with 1 N hydrochloric acid to pH=2 and the reaction product is taken up several times with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue is crystallised from ethyl acetate and hexane. The above results in 2.27 g of N² -t-butoxycarbonyl,N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionyl-L-alanine with a melting point of 108°-110° C. being obtained, which amounts to 88 per cent of the theoretical yield.

b. 1.036 g (2 mM) of N² -t-butoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionyl-L-alanine are dissolved in 10 ml of 4 N hydrogen chloride in dioxan and allowed to stand for 5 hours. Next, the solvents are evaporated and the residue is crystallised from a mixture of methanol and ethyl ether. 0.863 g of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionyl-L-aniline of a melting point of 178°-180° C. is obtained, which amounts to 99 per cent of the theoretical yield. MIC=0.1 ug/ml

EXAMPLES II-VII

Just as in Example I, the following derivatives of L-2,3-diaminopropanoic acid of the tripeptide structure have been obtained, as presented in the table below.

                  TABLE 1                                                          ______________________________________                                                                        mass ion,                                       Example                                                                               Name of derivative      m/z                                             ______________________________________                                         II     N.sup.3 --4-methoxyfumaroyl-L-2,3-diamino-                                                             358                                                    propanoyl-L-alanyl-L-alanine hydro-                                            chloride                                                                III    N.sup.3 -4-methoxyfumaroyl-L-2,3-diamino-                                                              478                                                    propanoyl-L-methionyl-L-methionine                                             hydrochloride                                                           IV     N.sup.3 -4-methoxyfumaroyl-L-2,3-diamino-                                                              386                                                    propanoyl-L-valyl-L-alanine hydro-                                             chloride                                                                V      N.sup.3 -4-methoxyfumaroyl-L-2,3-diamino-                                                              442                                                    propanoyl-L-leucyl-L-leucine-hydro-                                            chloride                                                                VI     N.sup.3 -4-methoxyfumaroyl-L-2,3-diamino-                                                              446                                                    propanoyl-L-methionyl-L-valine hydro-                                          chloride                                                                VII    N.sup.3 -4-methoxyfumaroyl-L-2,3-diamino-                                                              418                                                    propanoyl-L-alanyl-L-methionine                                                hydrochloride                                                           ______________________________________                                    

EXAMPLE VIII

a. 2.065 g (5 mM) N-hydroxysuccinoimide ester N² -t-butoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid in 10 ml of tetrafurane are added under intensive mixed to a cooled solution of 0.74 g (5 mM) of L-methionine an 0.42 g (5 mM) of sodium hydrogen carbonate in 10 ml of water and allowed to stand for 10 hours. Next,the solvent is evaporated, the residue dissolved in 10 ml of water and acidified with 1 N hydrochloric acid to a pH-value of 2, and the reaction product is several times extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue is crystallised from ethyl acetate and hexane. 1.96 g of N² -t-butoxycarbonyl, N³ -4-methoxyfumaryol-L-2,3-diaminopropanoyl-L-methionine with a melting point of 84°-86° C. are obtained, which accounts for 89 per cent of the theoretical yield.

b. 0.89 g (2 mM) of N² -t-butoxycarbonyl, N³ -4-methoxyfumaryl-L-2,3 diaminopropanoyl-L-methionine is dissolved in 10 ml of 4 N hydrogen chloride in dioxan and is allowed to stand for 3 hours at room temperature. Next, the solvents are evaporated and the residue crystallised from a mixture of methanol and ethyl ester. 0.714 g of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionine hydrochloride with a melting point of 184°-186° C. is obtained, which amounts to 94 per cent of the theoretical yield.

c. 0.381 g /1 mM/ N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionine hydrochloride is dissolved in 10 ml of methanol cooled down to a temperature of 0° C. and 0.3 ml of triethylamine is added. 0.346 g (1 mM) of N-hydroxysuccinoimide N-t-butoxycarbonyl-L-methionine dissolved in 10 ml of tetrahydrofuran is added to that solution under intensive mixing and the reaction mixture is allowed to stand for 5 hours. The further procedure is the same as in Example I. 0.485 g of N² -/N-t-butoxycarbonyl-L-methionyl/, N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionine with a melting point of 148°-150° C. is obtained, which amounts to 84 per cent of the theoretical yield.

d. 0.298 g (0.5 mM) N² -(N-t-butoxycarbonyl-L-methionyl), N³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methionine is dissolved in 10 ml of 4 N hydrogen chloride in dioxan and is allowed to stand for 4 hours at room temperature. Thereafter, the solvents are evaporated and the residue is crystallised from a mixture of methanol and ethyl ether. 0.246 g of N² -L-methionyl, n³ -4-methoxyfumaryl-L-2,3-diaminopropanoyl-L-methonine hydrochloride with a melting point of 205°-207° C. is obtained, which amounts to 96 per cent of the theoretical yield.

The MIC is 0.8 μg/ml.

EXAMPLES IX-XIV

Just as in Example XIII the following derivatives of L-2,3-diaminopropionic acid, having the tripeptide structure and presented in Table 2, have been obtained.

                  TABLE 2                                                          ______________________________________                                                                         mass ion,                                      Example                                                                               Name of derivatives      m/z                                            ______________________________________                                         IX     N.sup.2 --L-alanyl-, N.sup.3 -4-methoxyfumaroyl-L-                                                      418                                                   2,3-diaminopropanoyl-L-methionine hydro-                                       chloride                                                                X      N.sup.2 --L-alanyl, N.sup.3 -4-methoxyfumaroyl-L-2,3-                                                   358                                                   diaminopropanoyl-L-alanine hydrochloride                                XI     N.sup.2 --L-methionyl, N.sup.3 -4-methoxyfumaroyl-L-                                                    418                                                   2,3-diaminopropanoyl-L-alanine hydro-                                          chloride                                                                XII    N.sup.2 --L-valil, N.sup.3 -4-methoxyfumaroyl-L-2,3-                                                    414                                                   diaminopropanoyl-L-valine-hydrochloride                                 XIII   N.sup.2 --L-leucyl, N.sup.3 -4-methoxyfumaroyl-L-2,3-                                                   400                                                   diaminopropanoyl-L-alanine hydrochloride                                XIV    N.sup.2 -methionyl, N.sup.3 -4-methoxyfumaroyl-L-                                                       460                                                   2,3-diaminopropanoyl-L-leucine hydro-                                          chloride                                                                XV     N.sup.2 --L-norvalyl, N.sup.3 -4-methoxyfumaroyl-L-                                                     414                                                   2,3-diaminopropanoyl-L-norvaline hydro-                                        chloride                                                                ______________________________________                                    

EXAMPLE XVI

a. 0.7 ml of triethylamine and 1.27 g (5 mM) of n³ -4-methoxyfumaryl-L-2,3-diaminopropanoic hydrochloride dissolved in 5 ml of water is added to a cooled solution of 1.57 g (5 mM) of N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-L-norvaline in 20 ml of tetrahydrofurane under intensive mixing. The whole is mixed for 4 hours and the solvent is evaporated. The residue is dissolved in 10 ml of water, 1 N hydrochloric acid is added until a pH-value of 2 has been obtained and the reaction product is extracted several times with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulphate and the solvent is evaporated. The product is crystallised from a mixture of ethyl acetate and hexane.

1.7 g of N² -t-butoxy carbonyl-L-norvalyl, N³ -4-methoxyfumaroyl-L-2,3-diaminopropanoic acid or melting point of 68°-70° C. is obtained, which amounts to 83 per cent of the theoretical yield.

b. 0.83 g (2 mM) of N² -t-butoxycarbonyl-L-norvalyl, N³ -4-methoxyfumaroyl-L-2,3-diaminopropanoic acid is dissolved in 10 ml of 4 N hydrogen chloride in dioxan and allowed to stand for 4 hours at room temperature. Thereafter, the solvent is evaporated under reduced pressure and the residue is crystallised from a mixture of methanol and ethyl ether.

0.65 g of N² -L-norvalyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropanoioacidhydrochloride with a melting point of 188°-190° C. is obtained, which amounts to 93 per cent of the theoretical yield.

c. 0.3 ml of triethylamine and 0.351 g of (1 mM) N² -L-norvalyl, N³ -2-methoxyfumaroyl-L-2,3-diaminopropanoic hydrochloride dissolved in 10 ml of water are added to a cooled solution of 0.346 g (1 mM) N-hydroxysuccinoimide ester of N-t-butoxycarbonyl-L-methionine in 10 ml of tetrahydrofuran. The whole is mixed for 4-6 hours and the solvent is evaporated. The residue is dissolved in 10 ml of water, 1 N hydrochloric acid is added until pH=2 has been obtained and the reaction product is extracted with ethyl acetate. The organic layer is washed with water, dryed over magnesium sulphate and the solvent is evaporated. The product is crystallised from a mixture of ethyl ether and cyclohexane.

0.415 g of N² -(N-t-butoxycarbonyl-L-methionyl-L-norvalyl), N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid with a melting point of 118°-120° C. is obtained, which amounts to 76 per cent of the theoretical yield.

d. 0.273 g (0.5 mM) N² -(N-t-butoxycarbonyl-L-methionyl-L-norvalyl), N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid is dissolved in 5 ml of 4 N hydrogen chloride in dioxan and is allowed to stand at room temperature. Thereafter, the solvent is evaporated under reduced pressure and the residue is crystallised from a mixture of methanol and ethyl ether.

0.23 g of N² -L-methionyl-L-norvalyl, N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic hydrochloride with a melting point of 190°-192° C. is obtained, which amounts to 95 per cent of the theoretical yield. The MIC is 0.8 μg/ml.

EXAMPLES XVII-XXV

Just as in Example XV the following derivatives of L-2,3-diaminopropanoic acid, having the structure of tripeptides and presented in the table below, have been obtained.

    ______________________________________                                                                         Mass ion,                                      Example                                                                               Name of derivative       m/z                                            ______________________________________                                         XVII   N.sup.2 --L-methionyl-L-alanyl, N.sup.3 -4-methoxy-                                                     418                                                   fumaroyl-L-2,3-diaminopropanoic hydro-                                         chloride                                                                XVIII  N.sup.2 -sarcosyl-L-norvalyl, N.sup.3 -4-methoxy-                                                       404                                                   fumaroyl-L-2,3-diaminopropanoic hydro-                                         chloride                                                                XIX    N.sup.2 --L-leucyl-L-alanyl, N.sup.3 -4-methoxyfuma- 400                       royl-L-2,3-diaminopropanoic hydrochloride                               XX     N.sup.2 --L-valyl-L-methionyl, N.sup.3 -4-methoxy-                                                      446                                                   fumaroyl-L-2,3-diaminopropanoic hydro-                                         chloride                                                                XXI    N.sup.2 --L-norvalyl-L-norvalyl, N.sup.3 -4-methoxy-                                                    414                                                   fumaroyl-L-2,3-diaminopropanoic hydro-                                         chloride                                                                XXII   N.sup.2 --L-lysyl-L-norvalyl-N.sup.3 -4-methoxyfu-                                                      443                                                   maryl-L-2,3-diaminopropanoic dihydro-                                          chloride                                                                XXIII  N.sup.2 --L-ornithyl-L-norvylyl-N.sup.3 -4-methoxy-                                                     429                                                   furmaryl-L-2,3-diaminopropanoic dihydro-                                       chloride                                                                XXIV   N.sup.2 --L-2,4-diaminobutanoyl-L-norvalyl-                                                             415                                                   N.sup.3 -4-methoxyfumaroyl-L-2,3-diaminopro-                                   panoic dihydrochloride                                                  XXV    N.sup.2 --L-2,3-diaminopropanoyl-L-norvalyl-                                                            401                                                   N.sup.3 -4-methoxyfumaroyl-L-2,3-diaminopro-                                   panoic dihydrochloride                                                  ______________________________________                                     

We claim:
 1. A tripeptide of N³ -4-methoxyfumaryl-L-2,3-diaminopropanoic acid of the general formula ##STR7## where R is a hydrogen atom when R₁ is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, or R and R₁ have the same meaning and are the residue of monoaminomonocarboxylic aminoacid, selected from the group consisting of alanine, methionine, valine, leucine, norvaline, or R is the dipeptide residue containing the residue of alanine, methionine, valine, leucine, norvaline, lysine, ornithine, sarcosine, 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid, and R₁ is a hydroxide group. 